Patent applications WO 01/00610, WO 01/30774 and WO 01/68648, the content of each of which is incorporated herein by reference, describe compounds which are able to modulate NFκB. NFκB is a heterodimeric transcription factor which is able to activate a large number of genes which encode, inter alia, proinflammatory cytokines such as IL-1, IL-2, TNFα or IL-6. NFκB is present in the cytosol of cells, where it is complexed with its naturally occurring inhibitor IκB. Stimulation of the cells, for example by cytokines, leads to the IκB being phosphorylated and subsequently broken down proteolytically. This proteolytic breakdown leads to the activation of NFκB, which then migrates into the nucleus of the cell, where it activates a large number of proinflammatory genes.
In diseases such as rheumatoid arthritis (in connection with inflammation), osteoarthritis, asthma, cardiac infarction, Alzheimer's diseases or atherosclerosis, NFκB is activated to beyond the normal extent. The inhibition of NFκB is also of value in the treatment of cancer since it is used in such treatment to augment the cytostatic therapy. It has been demonstrated that pharmaceuticals such as glucocorticoids, salicylates or gold salts, which are used in the therapy of rheumatism, inhibit the NFκB-activating signal chain at various points or interfere directly with the transcription of the genes. The first step in said signal cascade is the breakdown of IκB. This phosphorylation is regulated by the specific IκB kinase.
Pharmaceuticals belonging to a large number of different substance groups are employed in treating acute and chronic pain. Despite this, the therapy of pain has still not been satisfactorily solved even today. This is due, in particular, to the fact that the analgesics which are on the market do not have a sufficiently powerful effect.
In an endeavor to obtain active compounds for treating pain, it has now been found that it is possible to use IκB-kinase inhibitors for this purpose. In particular, it has been possible to demonstrate, in the models employed, a strength of effect which is clearly superior to that of classical nonsteroidal anti-inflammatory agents.
The invention relates, therefore, to the use of IκB-kinase inhibitors for producing pharmaceuticals for treating pain.
The term “pain” is understood as meaning acute pains and chronic pains. The following are examples of chronic pains:
chronic musculoskeletal diseases, such as back pains,
pains associated with menstrual bleeding,
pains associated with osteoarthritis or rheumatoid arthritis,
pains associated with intestinal inflammation,
pains associated with cardiac muscle inflammation,
pains associated with multiple sclerosis,
pains associated with neuritis,
pains associated with carcinomas and sarcomas,
pains associated with AIDS,
pains associated with chemotherapy,
amputation pain,
trigeminus neuralgia,
headaches, such as migraine cephalalgia, or
neuropathic pains, such as post-herpes zoster neuralgia.
The following are examples of acute pains:
pains following injuries,
post-operative pains,
pains in association with an acute attack of gout, or
acute pains following jaw-bone surgery interventions.
Examples of IκB-kinase inhibitors are indole derivatives or benzimidazole derivatives as are described in the patent applications WO 01/00610 and WO 01/30774.